Search Images Maps Play YouTube News Gmail Drive More »
Sign in
Screen reader users: click this link for accessible mode. Accessible mode has the same essential features but works better with your reader.

Patents

  1. Advanced Patent Search
Publication numberUS4272537 A
Publication typeGrant
Application numberUS 06/165,313
Publication dateJun 9, 1981
Filing dateJul 2, 1980
Priority dateJul 2, 1980
Publication number06165313, 165313, US 4272537 A, US 4272537A, US-A-4272537, US4272537 A, US4272537A
InventorsOtto W. WOLTERSDORF, Jr., S. Jane deSolms, Robert L. Smith
Original AssigneeMerck & Co., Inc.
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
3-Amino-5-substituted-6-halo-N-(4,4-disubstituted-6-substituted-1,3,5-triazin-2-yl)-2-pyrazinecarboxamides
US 4272537 A
Abstract
This invention relates to 3-amino-5-substituted-6-halo-N-(4,4-disubstituted-6-substituted-1,3,5-triazin-2-yl)-2-pyrazinecarboxamides and processes for preparing same. The compounds are eukalemic/saluretic agents useful in the treatment of edema and hypertension.
Images(7)
Previous page
Next page
Claims(11)
What is claimed is:
1. A compound of the formula or the tautomeric form thereof ##STR5## wherein R is hydrogen, C1-5 alkyl, C2-5 alkenyl or C3-6 cycloalkyl;
R1 is hydrogen, C1-5 alkyl, C2-5 alkenyl or C3-6 cycloalkyl;
R2 is C1-5 alkyl;
R3 is C1-5 alkyl;
R2 and R3 can be joined with the carbon atom to which they are attached to form a 3-7 membered carbon ring;
X is halo;
Y is OH, SH, C1-5 alkoxy, C1-5 alkylthio and NR4 R5 wherein R4 is hydrogen or C1-5 alkyl and R5 is hydrogen, C1-5 alkyl, CN, CONH2, ##STR6## NO2 or NH2 and the pharmaceutical acid addition salts thereof.
2. A compound of the formula ##STR7## wherein R is hydrogen or C1-5 alkyl,
R1 is hydrogen or C1-5 alkyl,
R2 is methyl,
R3 is methyl,
X is chloro,
Y is OH, SH, C1-5 alkoxy, C1-5 alkylthio or cyanoamino and the pharmaceutically acceptable salts thereof.
3. A compound of claim 2 which is 3,5-diamino-6-chloro-N-(3,4-dihydro-4,4-dimethyl-6-methylthio-1,3,5-triazin-2-yl)-2-pyrazinecarboxamide.
4. A compound of claim 2 which is 3,5-diamino-6-chloro-N-(3,4-dihydro-4,4-dimethyl-6-mercapto-1,3,5-triazin-2-yl)-2-pyrazinecarboxamide hydrochloride.
5. A compound of claim 2 which is 3,5-diamino-6-chloro-N-(3,4-dihydro-4,4-dimethyl-6-cyanoamino-1,3,5-triazin-2-yl)-2-pyrazinecarboxamide.
6. A compound of claim 2 which is 3,5-diamino-6-chloro-N-(3,4-dihydro-4,4-dimethyl-6-ethoxy-1,3,5-triazin-2-yl)-2-pyrazinecarboxamide.
7. A compound of claim 2 which is 3,5-diamino-6-chloro-N-(3,4-dihydro-4,4-dimethyl-6-hydroxy-1,3,5-triazin-2-yl)-2-pyrazinecarboxamide.
8. A pharmaceutical composition useful in the treatment of edema and hypertension which comprises in combination with a pharmaceutically acceptable carrier, a compound or the tautomeric form of the formula: ##STR8## wherein R is hydrogen, C1-5 alkyl, C2-5 alkenyl or C3-6 cycloalkyl;
R1 is hydrogen, C1-5 alkyl, C2-5 alkenyl or C3-6 cycloalkyl;
R2 is C1-5 alkyl;
R3 is C1-5 alkyl;
R2 and R3 can be joined with the carbon atom to which they are attached to form a 3-7 membered carbon ring;
X is halo;
Y is OH, SH, C1-5 alkoxy, C1-5 alkylthio and NR4 R5 wherein R4 is hydrogen or C1-5 alkyl and R5 is hydrogen, C1-5 alkyl, CN, CONH2, ##STR9## NO2 or NH2 and the pharmaceutical acid addition salts thereof.
9. A pharmaceutical composition useful in the treatment of edema and hypertension which comprises in combination with a pharmaceutically acceptable carrier, a compound or the tautomeric form of the formula: ##STR10## wherein R is hydrogen or C1-5 alkyl,
R1 is hydrogen or C1-5 alkyl,
R2 is methyl,
R3 is methyl,
X is chloro,
Y is OH, SH, C1-5 alkoxy, C1-5 alkylthio or cyanoamino and the pharmaceutically acceptable salts thereof.
10. A method of treating edema or hypertension which comprises administering to a patient in need of such treatment a pharmaceutically effective amount of a compound of the formula: ##STR11## wherein R is hydrogen, C1-5 alkyl, C2-5 alkenyl or C3-6 cycloalkyl;
R1 is hydrogen, C1-5 alkyl, C2-5 alkenyl or C3-6 cycloalkyl;
R2 is C1-5 alkyl;
R3 is C1-5 alkyl;
R2 and R3 can be joined with the carbon atom to which they are attached to form a 3-7 membered carbon ring;
X is halo;
Y is OH, SH, C1-5 alkoxy, C1-5 alkylthio and NR4 R5 wherein R4 is hydrogen or C1-5 alkyl and R5 is hydrogen, C1-5 alkyl, CN, CONH2, ##STR12## NO2 or NH2 and the pharmaceutical acid addition salts thereof.
11. A method of treating edema or hypertension which comprises administering to a patient in need of such treatment a pharmaceutically effective amount of a compound of the formula: ##STR13## wherein R is hydrogen or C1-5 alkyl,
R1 is hydrogen or C1-5 alkyl,
R2 is methyl,
R3 is methyl,
X is chloro,
Y is OH, SH, C1-5 alkoxy, C1-5 alkylthio or cyanoamino and the pharmaceutically acceptable salts thereof.
Description
BACKGROUND OF THE INVENTION

The background to this invention, U.S. Pat. No. 3,313,813 patented Apr. 11, 1967 and issued to Edward J. Craoge, Jr., shows novel (3-amino-5,6-disubstituted-pyrazinoyl)guanidine compounds. The compounds of the '813 patent are useful because they possess diuretic and natriuretic properties. They differ from most of the known, effective diuretic agents, however, in that the compounds of the '813 patent selectively enhance the excretion of sodium ions while simultaneously causing a decrease in excretion of potassium ions. The potassium loss, which is caused by known diuretics, often results in a severe muscular weakness. Since the compounds of the '813 patent prevent the potassium depletion, they have this decided advantage as diuretics. As diuretic agents, they can be used for the treatment of edema, hypertension and other diseases or conditions known to be responsive to this therapy and are especially useful when used in combination with or concomitantly with potassium losing diuretic agents.

It has been found in U.S. Pat. No. 3,313,813 that the pyrazinoylguanidine compounds therein described when co-administered with other diuretic agents known to enhance the elimination of potassium ions along with sodium ions, will maintain the potassium ion excretion at approximately the normal or control rate and thus overcome this undesirable property of other diuretic agents.

In actuality, applicants' compounds in the instant case as further described, accomplish the objective previously achieved by using a combination of pyrazinoylguanidine compounds of the U.S. Pat. No. 3,313,813 with diuretic agents which cause elimination of sodium with concomitant excessive potassium elimination. Thus, the compounds of the instant case are effective eukalemic/saluretic agents. Since the compounds of the instant invention are thus eukalemic/saluretic agents, they constitute single entities which are useful for the treatment of edema and hypertension and other diseases or conditions known to be responsive to this therapy.

SUMMARY OF THE INVENTION

The instant case covers novel 3-amino-5-substituted-6-halo-N-(4,4-disubstituted-6-substituted-1,3,5-triazin-2-yl)-2-pyrazinecarboxamides and processes for making the same. The novel compounds of this invention are depicted in Formula I below: ##STR1## wherein R and R1 are the same or different and are hydrogen or C1-5 alkyl, C2-5 alkenyl or C3-6 cycloalkyl;

R2 and R3 are the same or different and are C1-5 alkyl;

R2 and R3 may also be joined with the carbon atom to which they are attached to form a 3-7 membered carbon ring;

X is halo such as chloro, fluoro, bromo or iodo;

Y is OH, SH, C1-5 alkoxy, C1-5 alkylthio and NR4 R5 wherein R4 is hydrogen or C1-5 alkyl and R5 is hydrogen, C1-5 alkyl, CN, CONH2, ##STR2## NO2 or NH2 and the pharmaceutically acceptable acid addition salts thereof.

The invention includes compounds which are the tautomeric form of the compounds of Formula I namely to tautomeric forms of the formula: ##STR3## wherein R, R1, X, R2, R3, R4 and R5 are as defined for Formula I and Y is as defined above minus a hydrogen atom.

In the above compounds, C1-5 alkyl means both branched chain and straight chain radicals such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, isopentyl and the like. C2-5 alkenyl is represented by allyl, propenyl and the like and C3-6 cycloalkyl is represented by cyclopropyl, cyclopentyl, cyclohexyl and the like.

Preferred compounds of this invention are those compounds of Formula I and the tautomeric form of Formula II wherein

R and R1 are hydrogen or C1-5 alkyl,

R2 and R3 are methyl,

X=Cl,

Y=OH, SH, C1-5 alkoxy, C1-5 alkylthio or cyanoamino and the pharmaceutically acceptable salts thereof.

The compounds of this invention as shown by Formula I and the preferred compounds discussed above are useful because they possess diuretic and natriuretic properties. In addition, they are useful eukalemic saluretics, in other words, the compounds of the instant case cause neither loss or abnormal retention of potassium ions. In contradistinction, the pyrazinoylguanidine compounds of U.S. Pat. No. 3,313,813 do cause a decrease in the excretion of potassium ions. However, other well known diuretics such as furosemide, chlorthalidone and acetazolamide cause an increase in potassium excretion which often results in muscular weakness. Applicants' compounds combine in a single agent the advantages of a combination of the known pyrazinoylguanidine diuretics of U.S. Pat. No. 3,313,813 which decrease potassium with the known diuretics which cause a potassium loss. Thus, the compounds of this invention maintain the excretion of potassium at approximately normal levels while causing an increased renal elimination of sodium ions and water which is the desirable characteristic of the diuretic.

Also covered within the scope of the above Formula I compounds and the preferred compounds are the pharmaceutically acceptable acid addition salts thereof. These salts can be made by reacting the free base with a pharmaceutically acceptable acid such as for example, hydrochloric acid, sulfuric acid, hydrobromic acid or isethionic acid. These salts, as stated above, are to be considered as included in this invention.

The products of this invention can be administered to patients (both human and animal) in the form of pills, tablets, capsules, elixirs, injectable preparations and the like. They can be administered either orally or parentally or any other feasible method as known to those skilled in the art such as intravenously or in the form of suppositories and the like.

The type of formulation to be administered can be comprised of one or more of the compounds of this invention as the only essential active ingredient of the pharmaceutical formulation. The formulation is merely combinations of the active ingredient mentioned with pharmaceutically inert carriers and the like.

The compounds of this invention are advantageously administered at a dosage range of from about 5 mg. to about one gram per day or a somewhat higher or lower dosage at the physician's discretion, preferably in subdivided amounts on a 2 to 4 times a day regimen and most preferably at a dosage range from 10 to 500 mg. per day. It will be realized by those skilled in the art that the dosage range for any particular patient (animal or human) will depend upon the severity of the disease treated, weight of the patient and any other condition which the physician or other person skilled in the art will take account of.

The compounds of Formula I can be prepared by any of the following processes which are depicted by four chemical reaction schemes.

In all four reaction schemes R, R1, R2, R3, R4, R5, X and Y are the same as is defined for Formulae I and II. ##STR4##

The process in Reaction I involves reacting an active pyrazinoic acid amide such as the imidazole amide III with a 2-amino-3,4-dihydro-1,3,5-triazine to obtain the desired product. The reaction is conducted in a suitable solvent such as dimethylformamide, dimethylsulfoxide and the like at a temperature of from 25 C. to the boiling temperature of the solvent but preferably from 50 C. to 100 C. The reaction is usually conducted with an excess of the triazine component and the desired product is isolated by filtration of the cooled reaction or by treatment of the reaction solution with water followed by filtration of the product.

In Reaction II, the methylthio triazine carboxamide starting material IV is reacted with hydrogen sulfide gas in an organic solvent such as pyridine at a temperature of from 0-50 C. for a period of 1-24 hours. The end product V is isolated from the reaction mixture by known means such as for example by treating the reaction mixture with water.

Similarly, the starting material IV can be dissolved in a solvent such as butanol and reacted with H2 NCN to yield the product shown as Compound VI in Reaction Scheme II. This reaction is generally carried out at a temperature of 50 to reflux temperature of the solvent for a time of about 1-24 hours. The product VI is isolated by known means such as for example by cooling the reaction and filtering the product.

In Reaction III, the 6-ethoxy triazine carboxamide starting material VII is reacted with trimethyl silyl iodide in an organic solvent such as sulfolane at a temperature of from 25-100 C. for a period of from 1-24 hours to yield 6-oxo triazine pyrazine carboxamide compounds.

Finally in Reaction IV starting material VIII is reacted with a ketone in a solvent such as dimethylformamide at 50 to reflux temperature of solvent for 1-24 hours to yield a similar 6-oxo end product shown as Compound IX.

The following examples are included to illustrate the preparation of compounds of this invention and also to illustrate the preparation of a representative dosage form.

EXAMPLE 1 3,5-Diamino-6-chloro-N-(3,4-dihydro-4,4-dimethyl-6-methylthio-1,3,5-triazin-2-yl)-2-pyrazinecarboxamide

To a solution of 3,5-diamino-6-chloropyrazinoic acid (1.13 g., 0.006 mole) in dimethylformamide (50 ml.) is added 1,1'-carbonyldiimidazole (0.972 g., 0.006 mole). The reaction mixture is stirred for 1 hour in a nitrogen atmosphere to form, in situ, 1-(3,5-diamino-6-chloropyrazinoyl)imidazole, which is treated with 2-amino-3,4-dihydro-4,4-dimethyl-6-methylthio-1,3,5-triazine. The reaction mixture is heated at 95 for 3 hours and cooled to give 1.3 g. of 3,5-diamino-6-chloro-N-(3,4-dihydro-4,4-dimethyl-6-methylthio-1,3,5-triazin-2-yl)-2-pyrazinecarboxamide which melts at 232-4 C.

Elemental analysis for C11 H15 ClN8 OS: Calcd: C, 38.54; H, 4.41; N, 32.69; Found: C, 38.39; H, 4.48; N, 32.64.

EXAMPLE 2 3,5-Diamino-6-chloro-N-(3,4-dihydro-4,4-dimethyl-6-mercapto-1,3,5-triazin-2-yl)-2-pyrazinecarboxamide hydrochloride

Hydrogen sulfide is slowly bubbled with a solution of 3,5-diamino-6-chloro-N-(3,4-dihydro-4,4-dimethyl-6-methylthio-1,3,5-triazin-2-yl)-2-pyrazinecarboxamide (1.0 g., 0.0029 mole) in pyridine (25 ml.) containing triethylamine (1.5 ml.) for a period of five hours. Nitrogen is bubbled into the reaction mixture to remove excess hydrogen sulfide which is then poured into ice water (100 ml.). The collected solid is dissolved in hot water (75 ml.) containing hydrochloric acid (0.5 ml.) then cooled to give 3,5-diamino-6-chloro-N-(3,4-dihydro-4,4-dimethyl-6-mercapto-1,3,5-triazin-2-yl)-2-pyrazincarboxamide hydrochloride which melts at 232 C. with decomposition.

Elemental analysis for C10 H13 ClN8 OS.HCl Calcd: C, 32.88; H, 3.86; N, 30.68; Found: C, 32.93; H, 4.42; N, 30.94.

EXAMPLE 3 3,5-Diamino-6-chloro-N-(3,4-dihydro-4,4-dimethyl-6-cyanoamino-1,3,5-triazin-2-yl)-2-pyrazinecarboxamide

A solution of 3,5-diamino-6-chloro-N-(3,4-dihydro-4,4-dimethyl-6-methylthio-1,3,5-triazin-2-yl)-2-pyrazinecarboxamide (1.0 g., 0.0029 mol) and cyanamide (0.7 g., 0.017 mol) in 1-butanol (50 ml.) is heated at reflux for 5 hours. The 3,5-diamino-6-chloro-N-(3,4-dihydro-4,4-dimethyl-6-cyanoamino-1,3,5-triazin-2-yl)-2-pyrazinecarboxamide which separates melts at 342 C. with decomposition.

Elemental analysis for C11 H10 ClN10 O; Calcd: C, 39.23; H, 3.89; Cl, 10.53; Found: C, 39.32; H, 4.04; Cl, 10.65.

EXAMPLE 4 3,4-Diamino-6-chloro-N-(3,4-dihydro-4,4-dimethyl-6-ethoxy-1,3,5-triazin-2-yl)-2-pyrazinecarboxamide Step A: 2-Amino-3,4-dihydro-4,4-dimethyl-6-ethoxy-1,3,5-triazine

To a solution of sodium (2.3 g., 0.1 gr. atom) in absolute ethanol (100 ml.) is added 2-amino-3,4-dihydro-4,4-dimethyl-6-methylthio-1,3,5-triazine (3.4 g., 0.02 mole) and the mixture is heated at reflux for 18 hours. The ethanol is distilled at reduced pressure and the residue dissolved in water (100 ml.) and extracted with ethyl acetate (3100 ml.) dried over potassium carbonate and evaporated in vacuo to give 1.3 g of 2-amino-3,4-dihydro-4,4-dimethyl-6-ethoxy-1,3,5-triazine which melts at 175-8 C. after crystallization from acetonitrile.

Elemental analysis for C7 H14 N4 O: Calcd: C, 49.39; H, 8.29; N, 32.92; Found: C, 48.84; H, 8.47; N, 33.42.

EXAMPLE 5 3,5-Diamino-6-chloro-N-(3,4-dihydro-4,4-dimethyl-6-hydroxy-1,3,5-triazin-2-yl)-2-pyrazinecarboxamide

To a stirred solution of 3,5-diamino-6-chloro-N-(3,4-dihydro-4,4-dimethyl-6-ethoxy-1,3,5-triazin-2-yl)-2-pyrazinecarboxamide (0.55 g., 0.0016 mole) in sulfolane (10 ml.) is added trimethylsilyl iodide (1.5 ml.). The reaction mixture is stirred for 5 hours at 45 C., poured into ice water (30 ml.) containing hydrochloric acid (1.5 ml.), then extracted with chloroform (215 ml.) The aqueous layer is made basic with ammonia to give 420 mg. of 3,5-diamino-6-chloro-N-(3,4-dihydro-4,4-dimethyl-6-hydroxy-1,3,5-triazin-2-yl)-2-pyrazinecarboxamide which melts at 266-8 C. after reprecipitation from dilute hydrochloric acid with ammonia.

Elemental analysis for C10 H13 ClN8 O2 ; Calcd: C, 38.41; H, 4.19; N, 35.83; Found: C, 38.40; H, 4.25; N, 35.44.

EXAMPLE 6 3,5-Diamino-6-chloro-N-(3,4-dihydro-4,4-dimethyl-6-hydroxy-1,3,5-triazin-2-yl)-2-pyrazinecarboxamide Step A: 2-Amino-3,4-dihydro-4,4-dimethyl-6-hydroxy-1,3,5-triazine

To a solution of 2-amino-3,4-dihydro-4,4-dimethyl-6-ethoxy-1,3,5-triazine (2.2 g.) in sulfolane (30 ml.) is added trimethylsilyl iodide (12 ml.). The reaction mixture is heated at 50 C. for four hours then poured into 50 ml of ice water containing 2 ml. of conc. HCl. The solution is extracted with chloroform then the aqueous layer is distilled in vacuo to a viscous syrup which upon treatment with 2-propanol and cooling deposits 2.1 g. of product hydrochloride which is dissolved in 3 ml. of water and treated with 2 ml. of conc. ammonia to give 1.1 g. of 2-amino-3,4-dihydro-4,4-dimethyl-6-hydroxy-1,3,5-triazine which melts above 300 C.

Elemental Analysis for C5 H10 N4 O: Calc.: C, 42.24; H, 7.09; N, 39.41; Found: C, 42.10; H, 7.51; N, 39.20.

Step B: 3,5-Diamino-6-chloro-N-(3,4-dihydro-4,4-dimethyl-6-hydroxy-1,3,5-triazin-2-yl)-2-pyrazinecarboxamide

To a solution of 3,5-diamino-6-chloropyrazinoic acid (0.92 g., 0.0049 mole) in dimethylformamide (40 ml.) is added 1,1'-carbonyldiimidazole (0.80 g., 0.0049 mol). The reaction mixture is stirred for 2 hours in a nitrogen atmosphere to form, in situ, 1-(3,5-diamino-6-chloropyrazinoyl) imidazole which is treated with 2-amino-3,4-dihydro, 4,4-dimethyl-6-hydroxy-1,3,5-triazine (1.1 g., 0.0076 mole). The reaction mixture is heated for 3 hours at 95 C., and treated with ice to give 1.3 g. of 3,5-diamino-6-chloro-N-(3,4-dihydro-4,4-dimethyl-6-hydroxy-1,3,5-triazin-2-yl)-2-pyrazinecarboxamide which melts at 266-8 C.

Elemental analysis for C10 H17 ClN8 O2 ; Calc: C, 38.41; H, 4.19; N, 35.83; Found: C, 38.12; H, 4.51; N, 34.89.

EXAMPLE 7 3,5-Diamino-6-chloro-N-(3',4'-dihydro-6'-hydroxy-4-methylspirocyclohexane[1,4']-1,3,5-triazin-2-yl)-2-pyrazinecarboxamide

A solution of 3,5-diamino-6-chloro-N-[[(aminocarbonyl)amino]iminomethyl]-2-pyrazinecarboxamide (0.5 g., 0.0018 mole) and 4-methylcyclohexanone (0.5 ml.) in dimethylformamide (10 ml.) is heated at 95 C. for 20 hours. The reaction mixture is treated with 20 ml. of 2-propanol, filtered, the filtrate distilled at reduced pressure to a volume of 2 ml. and chromatographed on silica gel to give 3,5-diamino-6-chloro-N-(3',4'-dihydro-6'-hydroxy-4-methylspirocyclohexane]1,4']-1,3,5-triazin-2-yl)-2-pyrazinecarboxamide which melts at 274 C.

Elemental analysis for C14 H19 ClN8 O2 : Calc.: C, 45.84; H, 5.22; Cl, 9.67; Found: C, 45.40; H, 5.17; Cl, 9.63.

EXAMPLE 8

Compressed Tablet containing 50 mg. of active ingredient.

______________________________________                Per Tablet, Mg.______________________________________3,5-diamino-6-chloro-N-(3,4-dihydro-4,4-dimethyl-6-methyl-thio-1,3,5-triazin-2-yl)-2-pyrazinecarboxamide     50Calcium phosphate dibasic                  200Ethyl cellulose (as 5% solution in ethanol)                   5Unmixed granulation    255Add:Starch, corn            14Magnesium stearate      1                  270______________________________________

Directions: Mix the active ingredient above and calcium phosphate and reduce to a No. 60 mesh powder. Granulate with Ethocel in alcohol and pass the wet granulation through a No. 10 screen. Dry the granulation at 110 F. for 12-18 hours. Dry grind to a No. 20 mesh. Incorporate the "adds" and compress into tablets each weighing 270 mg.

EXAMPLE 9

Dry filled capsule containing 50 mg. of active ingredient.

______________________________________              Per capsule, mg.______________________________________3,5-diamino-6-chloro-N-(3,4-dihydro-4,4-dimethyl-6-mercapto1,3,5-triazin-2-yl)-2-pyrazine-carboxamide hydrochloride                 50Lactose              273Magnesium stearate    2Mixed powders        325______________________________________

Mix the active ingredient above, lactose, and magnesium stearate and reduce to a No. 60 mesh powder. Encapsulate, filling 325 mg. in each No. 2 capsule.

The above formulations can be employed to prepare compressed tablets or capsules of other novel compounds of this invention hereinbefore described.

EXAMPLE 10

Combination dosage form in dry filled capsule

______________________________________              Per capsule, mg.______________________________________3,5-diamino-6-chloro-N-(3,4-dihydro-4,4-dimethyl-6-cyano-amino-1,3,5-triazin-2-yl)-2-pyrazinecarboxamide   50Magnesium stearate    2Lactose              223Mixed powders        275______________________________________

Mix all of the above ingredients, reduce to a No. 60 mesh powder and encapsulate, filling 275 mg. in each No. 2 capsule.

The above examples describe the preparation of certain compounds which are illustrative of the novel compounds of this invention, and certain specific dosage forms suitable for administering the novel compounds, it is to be understood that the invention is not to be limited to the specific compounds described in the examples or by the specific reaction conditions described for the preparation of these compounds or by the specific ingredients included in the pharmaceutical preparations, but is to be understood to embrace variations and modifications thereof which fall within the scope of the appended claims.

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US3840538 *Apr 4, 1973Oct 8, 1974Ciba Geigy Corp1-(4',6'-dichloro-s-triazin-2-ylcarbamoyl)-2-methoxycarbonylamino-benzimidazole
US4085211 *Sep 13, 1976Apr 18, 1978Merck & Co., Inc.Pyrazinecarboxamides and processes for preparing same
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US4317822 *Feb 9, 1981Mar 2, 1982Merck & Co., Inc.3-Amino-5-substituted-6-halo-N-(3,4-dihydro-6-substituted-1,3,5-triazin-2-yl)2-pyrazinecarboxamides
US4413147 *Apr 14, 1982Nov 1, 1983The Halcon Sd Group, Inc.Conversion of isobutane to methacrolein
US4906633 *May 26, 1988Mar 6, 1990Ici Americas Inc.Pyrazine amides
US4910202 *May 26, 1988Mar 20, 1990Ici Americas Inc.Aminomethylphenolic pyrazines
US4980352 *May 19, 1989Dec 25, 1990Ici Americas Inc.Gem-dimethyl substituted bicyclic compounds useful as eukalemic diuretics
US7745442Aug 18, 2004Jun 29, 2010Parion Sciences, Inc.Methods of reducing risk of infection from pathogens
US8039472Dec 10, 2008Oct 18, 2011Novartis AgPyrazine-2-carboxamide derivatives to treat diseases mediated by blockade of the epithelial sodium channel
US8314105Aug 8, 2007Nov 20, 2012Parion Sciences, Inc.Methods of reducing risk of infection from pathogens
US8669262Jun 26, 2012Mar 11, 2014Parion Sciences, Inc.3,5-diamino-6-chloro-N-(N-(4-(4-(2-(hexyl(2,3,4,5,6-pentahydroxyhexyl)amino)ethoxy)phenyl)butyl)carbamimidoyl)pyrazine-2-carboxamide
US8697687Sep 13, 2012Apr 15, 2014Novartis AgTreating diseases mediated by blockade of the epithelial sodium channel with pyrazine-2-carboxamide derivatives
US9139586 *Feb 21, 2014Sep 22, 2015Novartis AgTreating diseases mediated by blockade of the epithelial sodium channel with pyrazine-2-carboxamide derivatives
US20100130506 *Dec 10, 2008May 27, 2010Novartis AgOrganic Compounds
US20110237572 *Sep 29, 2011Novartis AgTreating diseases mediated by blockade of the epithelial sodium channel with pyrazine-2-carboxamide derivatives
US20140171421 *Feb 21, 2014Jun 19, 2014Novartis AgTreating diseases mediated by blockade of the epithelial sodium channel with pyrazine-2-carboxamide derivatives
EP0293170A1 *May 24, 1988Nov 30, 1988Ici Americas Inc.Aminomethylphenolic pyrazines, their preparation and use
EP0293171A1 *May 24, 1988Nov 30, 1988Ici Americas Inc.Pyrazinamide derivatives
EP2444120A1 *Dec 9, 2008Apr 25, 2012Novartis AGSpirocyclic amiloride analogues as ENac blockers
EP2520574A1 *Dec 9, 2008Nov 7, 2012Novartis AGAmiloride analogues substituted on the cyclic guanidine moiety as ENaC blockers for treating respiratory diseases
WO2009074575A2 *Dec 9, 2008Jun 18, 2009Novartis AgOrganic compounds
WO2009074575A3 *Dec 9, 2008Aug 13, 2009Novartis AgOrganic compounds
Classifications
U.S. Classification514/245, 544/212, 544/207
International ClassificationC07D251/10
Cooperative ClassificationC07D251/10
European ClassificationC07D251/10